This invention relates to an antibacterial compound useful for a medicament, a veterinary drug, a drug for fisheries or an antibacterial preservative, and to an antibacterial agent and an antibacterial preparation, which contain the compound.
Since the discovery of norfloxacin, antibacterial activity and pharmacokinetics after administration of quinolone antibacterial agents have been improved, and many compounds are now used in the clinical field as chemotherapeutic agents which are effective in almost systemic infectious diseases.
In recent years, generation of bacteria having low sensitivity to quinolone synthetic antibacterial agents has been increasing in the field of clinics. For example, like the case of Staphylococcus aureus (MRSA) which is non-sensitive to xcex2-lactam antibiotics, a case has been increasing in which a bacterium originally resistant to drugs other than quinolone antibacterial agents becomes low-sensitive to quinolone antibacterial agents too. In consequence, development of a drug having further high efficacy has been called for in the field of clinics. On the other hand, it has been revealed that quinolone synthetic antibacterial agents cause a side effect in which severe convulsion is induced when a non-steroidal anti-inflammatory drug is simultaneously used, as well as other side effects such as phototoxicity and the like, so that development of a quinolone synthetic antibacterial agent having higher safety has also been called for in the field.
In view of the above, the inventors of the present invention have conducted intensive studies with the aim of providing an excellent compound which can satisfy the aforementioned requirements. As a result of the efforts, it was found that a substituted cyclobutylamine derivative represented by the formula (I) described below, a salt thereof and a hydrate thereof are possessed of excellent antibacterial action upon broad range of Gram-negative and Gram-positive bacteria, can show particularly strong antibacterial activity upon quinolone-resistant bacteria including MRSA, and have excellent pharmacokinetics and safety, thereby resulting in the accomplishment of the present invention.
Accordingly, the present invention relates to a compound represented by the following formula (I), its salt or hydrates thereof: 
{wherein R1 and R2, each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms (excluding a case in which R1 and R2 are both hydrogen atoms),
wherein the alkyl group may have one or more substituent selected from the group consisting of a hydroxyl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms,
R3 and R4, each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
wherein the alkyl group may have one or more substituent selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms,
n is an integer of 1 or 2,
Q is a partial structure represented by the following formula: 
[wherein R5 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms,
R6 represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms,
wherein R6 and the aforementioned R5 may together form a cyclic structure including a part of the mother nucleus, and the thus formed ring may contain a sulfur atom as a ring constituting atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent, R7 represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms,
wherein the amino group may have one or more substituent(s) selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms,
X1 represents a halogen atom or a hydrogen atom,
A1 represents a nitrogen atom or a partial structure represented by the following formula (II): 
(wherein X2 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms,
wherein the amino group may have one or more substituent selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms, and
X2 and the aforementioned R5 may together form a cyclic structure including a part of the mother nucleus, and the thus formed ring may contain an oxygen atom, a nitrogen atom or a sulfur atom as a ring constituting atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent),
A2 and A3, each represents a nitrogen atom or a carbon atom,
wherein A2 and A3 together with carbon atoms to which they are linked form a partial structure: 
or a partial structure: 
Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and phenyl group]}.
The present invention also relates to:
the aforementioned compound, its salt or hydrates thereof in which a partial structure resulting from the exclusion of Q from the formula (I) is a stereochemically pure compound;
the aforementioned compound, its salt or hydrates thereof in which Q in the formula (I) is a compound having a structure represented by the following formula: 
{wherein R5 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms,
R6 represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms,
wherein R6 and the aforementioned R5 may together form a cyclic structure including a part of the mother nucleus, and the thus formed ring may contain a sulfur atom as a ring consituting atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent, R7 represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms,
wherein the amino group may have one or more substituent selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms,
X1 represents a halogen atom or a hydrogen atom,
A1 represents a nitrogen atom or a partial structure represented by the following formula (II): 
(wherein X2 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms,
wherein the amino group may have one or more substituent selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms, and
X2 and the aforementioned R5 may together form a cyclic structure including a part of the mother nucleus, and the thus formed ring may contain an oxygen atom, a nitrogen atom or a sulfur atom as a ring constituting atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent), and
Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group};
the aforementioned compound, its salt or hydrates thereof in which Q in the formula (I) is a compound having a structure represented by the following formula: 
{wherein R5 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms,
R6 represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms,
wherein R6 and the aforementioned R5 may together form a cyclic structure including a part of the mother nucleus, and the thus formed ring may contain a sulfur atom as a ring constituting atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent, R7 represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms,
wherein the amino group may have one or more substituent selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms,
X1 represents a halogen atom or a hydrogen atom,
A1 represents a nitrogen atom or a partial structure represented by the following formula (II): 
(wherein X2 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms,
wherein the amino group may have one or more substituent selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms, and
X2 and the aforementioned R5 may together form a cyclic structure including a part of the mother nucleus, and the thus formed ring may contain an oxygen atom, a nitrogen atom or a sulfur atom as a ring constituting atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent), and
Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group};
the aforementioned compound, its salt or hydrates thereof in which Q in the formula (I) is a 6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-10-yl group 
the aforementioned compound, its salt or hydrates thereof in which Q in the formula (I) is a 5-amino-3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinolin-7-yl group 
the aforementioned compound, its salt or hydrates thereof in which Q in the formula (I) is a 3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinolin-7-yl group 
the aforementioned compound, its salt or hydrates thereof in which Q in the formula (I) is a 5-amino-3-carboxy-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinolin-1-yl group 
the aforementioned compound, its salt or hydrates thereof in which R5 is a halogenocyclopropyl group;
the aforementioned compound, its salt or hydrates thereof in which the halogenocyclopropyl group is a 1,2-cis-halogenocyclopropyl group;
the aforementioned compound, its salt or hydrates thereof in which the halogenocyclopropyl group is a stereochemically pure substituent;
the aforementioned compound, its salt or hydrates thereof in which the halogenocyclopropyl group is a (1R,2S)-2-halogenocyclopropyl group;
the aforementioned compound, its salt or hydrates thereof in which the halogen atom of the halogenocyclopropyl group is a fluorine atom;
the aforementioned compound, its salt or hydrates thereof in which the compound of formula (I) is a stereochemically pure compound;
5-amino-7-[3-(3-amino-1-fluorocyclobutan-3-yl)pyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or hydrates thereof;
7-[3-(3-amino-1-fluorocyclobutan-3-yl)pyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or hydrates thereof;
5-amino-7-[3-(3-amino-1-fluorocyclobutan-3-yl)pyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or hydrates thereof;
7-[3-(3-amino-1,1-difluorocyclobutan-3-yl)pyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or hydrates thereof;
5-amino-7-[3-(3-amino-1,1-difluorocyclobutan-3-yl)pyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or hydrates thereof;
a pharmaceutical composition which comprises the aforementioned compound, its salt or hydrates thereof as an active ingredient; and
an antibacterial agent which comprises the aforementioned compound, its salt or hydrates thereof as an active ingredient.
The other objects and advantages of the present invention will be made apparent as the description progresses.
Each of the substituent groups of the compound of the present invention represented by the formula (I) is described in the following.
The substituents R1 and R2, each is independently a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms (excluding a case in which R1 and R2 are both hydrogen atoms), wherein the alkyl group may have one or more substituent selected from the group consisting of a hydroxyl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms.
As the halogen atom, fluorine or chlorine atom is preferable, and fluorine atom is particularly preferable.
The alkyl group may be either straight or branched group having 1 to 6 carbon atoms, and its preferred examples include methyl group, ethyl group, normal propyl group and isopropyl group.
The alkoxyl group may be either straight or branched group having 1 to 6 carbon atoms, and its preferred examples include methoxyl group and ethoxyl group.
The alkylthio group may be either straight or branched group having 1 to 6 carbon atoms, and its preferred examples include methylthio group and ethylthio group.
When an alkyl group having 1 to 6 carbon atoms has a hydroxyl group as a substituent, the alkyl group may be either straight or branched form, and the substituting position of hydroxyl group may preferably be on the terminal carbon atom of the alkyl group. Preferred examples of the alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group include hydroxymethyl group, 2-hydroxyethyl group and 3-hydroxypropyl group.
When an alkyl group having 1 to 6 carbon atoms has a halogen atom as a substituent, the alkyl group may be either straight or branched form, and fluorine atom is preferable as the halogen atom. With regard to the number of fluorine atoms, it may be any one of from mono-substitution to perfluoro substitution. Its examples include monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and the like groups.
When an alkyl group having 1 to 6 carbon atoms has an alkoxyl group as a substituent, each of the alkyl moieties may be either straight or branched form, and an alkoxymethyl or alkoxyethyl group is preferable. Its more preferred examples include methoxymethyl group, ethoxymethyl group and 2-methoxyethyl group.
A characteristic feature of the present invention is that one or two fluorine atoms are present on the cyclobutyl ring of the formula (I).
Particularly preferred examples of the combination of R1 and R2 include a case in which one of R1 and R2 is a hydrogen atom and the other one is a fluorine atom and a case in which both of R1 and R2 are fluorine atoms. In this connection, when the substituent group R1 and the substituent group R2 are different from each other, the carbon atoms to which R1 and R2 are linked become asymmetric carbons to form isomers, and all of such isomers are included in the present invention.
The substituent groups R3 and R4, each is independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group may have one or more substituent selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms.
The alkyl group may be either straight or branched group having 1 to 6 carbon atoms, and its preferred examples include methyl group, ethyl group, normal propyl group and isopropyl group.
When an alkyl group has a hydroxyl group as a substituent, the alkyl group may be either straight or branched group having 1 to 6 carbon atoms, and the hydroxyl group may preferably be positioned on the terminal carbon atom of the alkyl group. As the alkyl group having hydroxyl group, a group having carbon atoms of up to 3 is preferable, and hydroxymethyl group, 2-hydroxyethyl group and 3-hydroxypropyl group and the like are more preferable.
When an alkyl group has a halogen atom as a substituent, the alkyl group may be either straight or branched group having 1 to 6 carbon atoms, and a fluorine atom is preferable as the halogen atom. With regard to the number of fluorine atoms, it may be any one of from mono-substitution to perfluoro substitution. Its examples include monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and the like groups.
When an alkyl group has an alkylthio group as a substituent, the alkyl group may be either straight or branched form having 1 to 6 carbon atoms and the alkylthio group may also be either straight or branched form having 1 to 6 carbon atoms. As the alkyl group having an alkylthio group, an alkylthiomethyl group, an alkylthioethyl group or an alkylthiopropyl group is preferable, and the alkylthio group may preferably has 1 to 3 carbon atoms. Its more preferred examples include methylthiomethyl group, ethylthiomethyl group and methylthioethyl group.
When an alkyl group has an alkoxyl group as a substituent, the alkyl group may be either straight or branched form having 1 to 6 carbon atoms and the alkoxyl group may also be either straight or branched form having 1 to 6 carbon atoms. As the alkyl group having an alkoxyl group, an alkoxymethyl group, an alkoxyethyl group and an alkoxypropyl group are preferable, and the alkoxyl group may preferably has carbon atoms of up to 3. Its most preferred examples include methoxymethyl group, ethoxymethyl group and methoxyethyl group.
The symbol n is an integer of 1 or 2.
Q is a partial structure represented by the following formula. 
In the above formula, A2 and A3, each represents a nitrogen atom or a carbon atom, wherein A2 and A3 together with carbon atoms to which they are linked form a partial structure: 
or a partial structure: 
A condensed heterocyclic partial structure represented by the following formula: 
is preferred as the structure of Q.
The substituent R5 is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms.
In this case, ethyl group is preferable as the alkyl group having 1 to 6 carbon atoms, and vinyl group or 1-isopropenyl group is preferable as the alkenyl group having 2 to 6 carbon atoms. 2-Fluoroethyl group is preferable as the halogenoalkyl group having 1 to 6 carbon atoms.
Cyclopropyl group is particularly preferable as the cyclic alkyl group, and a halogen atom, particularly fluorine atom, is preferable as its substituent.
Examples of the aryl group which may have a substituent include phenyl or the like group which may have 1 to 3 substituents selected from the group consisting for example of fluorine, chlorine, bromine or the like halogen atom, hydroxyl group, amino group, nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms, and its preferred illustrative examples include phenyl group, 2-fluorophenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-fluoro-4-hydroxyphenyl group, 3-amino-4,6-difluorophenyl group and 4,6-difluoro-3-methylaminophenyl group.
The heteroaryl group is a substituent derived from a five-membered or six-membered aromatic heterocyclic compound which contains one or more hetero-atoms selected from nitrogen atom, oxygen atom and sulfur atom. Its examples include pyridyl, pyrimidyl and the like groups. As a substituent on these rings, a alkyl group, a halogen atom or the like is preferable.
Methoxyl group is preferable as the alkoxyl group having 1 to 6 carbon atoms. Methylamino group is preferable as the alkylamino group having 1 to 6 carbon atoms.
As the substituent R5, a cyclic alkyl group which may have a substituent is preferable, and cyclopropyl group or a 2-halogenocyclopropyl group is particularly preferable.
The halogenocyclopropyl group cited as a preferred example of the substituent R5 is described in detail.
As the substituting halogen atom, fluorine atom and chlorine atom can be exemplified, and fluorine atom is particularly preferable.
As the stereochemical environment at this moiety, it is particularly preferable that the halogen atom and the pyridonecarboxylic acid moiety are in cis-configuration in respect of the cyclopropane ring.
So-called antipode isomers exist solely by the cis-2-halogenocyclopropyl moiety of R5, and strong antibacterial activity and high safety have been observed in all of these isomers.
The substituent R6 is a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, or R5 and R6 may together form a hydrocarbon cyclic structure including a part of the mother nucleus (namely by including A2 to which R5 is linked and the carbon atom to which R6 is linked). The thus formed ring may contain a sulfur atom as a ring constituting atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent. The ring to be formed herein may have a size of from four-membered ring to six-membered ring, and the ring may be saturated, partially saturated or unsaturated. Its examples are shown below. 
(In the above formulae, R56 means a hydrogen atom or an alkyl group, and A1, Y, X1 and R7 are as defined in the formula (I).)
The substituent R7 is a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, wherein the amino group may have one or two substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 6 carbon atoms.
The alkyl group may be either straight or branched group having 1 to 6 carbon atoms and its preferred examples include methyl group, ethyl group, normal propyl group and isopropyl group. The alkenyl group may be either straight or branched group having 2 to 6 carbon atoms and is preferably vinyl group. The alkynyl group may be either straight or branched group having 2 to 6 carbon atoms and is preferably ethynyl group. Fluorine atom is particularly preferable as the halogen of the halogenomethyl group, and its number may be from 1 to 3. The alkoxyl group may have 1 to 6 carbon atoms and is preferably methoxyl group.
The substituent R7 is preferably hydrogen atom, an alkyl group or amino group, of which methyl group or unsubstituted amino group is more preferred.
When the substituent R7 is amino group, hydroxyl group or thiol group, these groups may be protected with usually used protective groups.
Examples of such protective groups include tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and the like alkoxycarbonyl groups, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, para-nitrobenzyloxycarbonyl and the like aralkyloxycarbonyl groups, acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl, benzoyl and the like acyl groups, tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, triphenylmethyl and the like alkyl or aralkyl groups, methoxymethyl, tert-butoxymethyl, tetrahydropyranyl, 2,2,2-trichloroethoxymethyl and the like ethers and trimethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, tribenzylsilyl, tert-butyldiphenylsilyl and the like silyl groups. Compounds whose substituents are protected with these protective groups are particularly useful as production intermediates.
The substituent X1 is a halogen atom or hydrogen atom, and fluorine atom is preferable as the halogen atom. Among these atoms, fluorine or hydrogen is preferable as the substituent.
When A1 is a partial structure represented by the following formula (II), 
X2 is a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, wherein the amino group may have one or two substituents selected from the group consisting of formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms.
The alkyl group may be either straight or branched group having 1 to 6 carbon atoms and its preferred examples include methyl group, ethyl group, normal propyl group and isopropyl group. The alkenyl group may be either straight or branched group having 2 to 6 carbon atoms and is preferably vinyl group. The alkynyl group may be either straight or branched group having 2 to 6 carbon atoms and is preferably ethynyl group. Fluorine atom is particularly preferable as the halogen of the halogenomethyl group, and its number may be from 1 to 3. The alkoxyl group may have 1 to 6 carbon atoms and is preferably methoxyl group. Fluorine atom is particularly preferable as the halogen of the halogenomethoxyl group, and its number may be from 1 to 3.
Among these substituents, a halogen atom, an alkyl group or an alkoxyl group is preferable, and fluorine atom, methyl group or methoxyl group is more preferable.
In addition, X2 and the aforementioned R5 may together form a hydrocarbon cyclic structure (size of the ring may be from four-membered ring to seven-membered ring, and the ring may be saturated, partially saturated or unsaturated) including a part of the mother nucleus (namely including the carbon atom to which X2 is linked and A2 to which R5 is linked), and the thus formed ring may contain oxygen atom, nitrogen atom or sulfur atom as a ring constituting atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent. Its examples are shown below. 
(In the above formulae, G is an oxygen atom, a sulfur atom or Cxe2x95x90O, and Y, X1, R6 and R7 are as defined in the formula (I).)
A structure of the following formula: 
is preferable as Q.
When Q is the just described partial structure and A1 is a partial structure of the formula (II), a preferred combination of R7 and X2 is a case in which R7 is an amino group, a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 6 carbon atoms and X2 is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogenomethoxyl group or a hydrogen atom.
A more preferred combination is a case in which R7 is an amino group, a hydrogen atom, a hydroxyl group or a methyl group and X2 is a fluorine atom, a methyl group, a methoxyl group, a difluoromethoxyl group or a hydrogen atom.
A most preferred combination is a case in which R7 is an amino group, a hydrogen atom, a hydroxyl group or a methyl group and X2 is a fluorine atom, a methyl group or a methoxyl group.
For these R7 and X2 groups, fluorine atom is preferable as X1.
When the substituents X1 and X2 are halogen atoms, X1 is particularly preferably fluorine atom and X2 is preferably fluorine atom or chlorine atom.
When Q is a structure represented by the following formula: 
and A1 is a partial structure of the formula (II), a preferred combination of R7 and X2 is a case in which R7 is an amino group, a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 6 carbon atoms and X2 is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogenomethoxyl group or hydrogen atom.
A more preferred combination is a case in which R7 is an amino group, a hydrogen atom, a hydroxyl group or a methyl group and X2 is a fluorine atom, a methyl group, a methoxyl group, a difluoromethoxyl group or a hydrogen atom.
A most preferred combination is a case in which R7 is an amino group, a hydrogen atom, a hydroxyl group or a methyl group and X2 is a fluorine atom, a methyl group or a methoxyl group.
When the substituents X1 and X2 are halogen atoms, X1 is particularly preferably a fluorine atom and X2 is preferably a fluorine atom or a chlorine atom.
When diastereomers are present in a compound of formula (I) of the present invention, and when such an inventive compound is administered to human and animals, it is preferable to administer a compound which comprises a single diastereomer. The term xe2x80x9csinglexe2x80x9d of xe2x80x9ccomprised of a single diastereomerxe2x80x9d as used herein means not only a case in which it is completely free from the other diastereomer but also a case in which it is in a chemically pure degree. In other words, it is interpretable that the other diastereomer may be present in such a degree that it does not exert influences upon physical constants and physiological activities of the compound.
Also, the term xe2x80x9cstereochemically purexe2x80x9d as used herein means that, when a compound or the like exists in a plurality of isomer forms due to the presence of asymmetric carbon atoms, the compound is comprised of only one of them. The term xe2x80x9cpurexe2x80x9d in this case can also be considered in the same manner as the term xe2x80x9csinglexe2x80x9d described above.
The pyridonecarboxylic acid derivative of the present invention may be used either in its free form or as an acid addition salt or a salt of its carboxyl group. Examples of the acid addition salt include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate and the like inorganic acid salts, or acetate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, maleate, fumarate, lactate and the like organic acid salts.
The salt of carboxyl group may be either inorganic or organic salt, and its illustrative examples include lithium salt, sodium salt, potassium salt and the like alkali metal salts, magnesium salt, calcium salt and the like alkaline earth metal salts, ammonium salt, or triethylamine salt, N-methylglucamine salt, tris-(hydroxylmethyl)aminomethane salt and the like.
Also, these free form, acid addition salts and salts of carboxyl group of the pyridonecarboxylic acid derivative may be present as hydrates.
On the other hand, a quinolone derivative whose carboxylic acid moiety is an ester is useful as a synthesis intermediate or a prodrug. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters and phenyl esters are useful as synthesis intermediates.
Also, the ester to be used as a prodrug is an ester which is easily cleaved in the living body to give free form of carboxylic acid, and its illustrative examples include acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, choline ester, dimethylaminoethyl ester, 5-indanyl ester, phthalidinyl ester, and 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester, 3-acetoxy-2-oxobutyl eater or the like oxoalkyl ester.
The compound of the present invention represented by the formula (I) can be produced by various method, and, in an preferred example of these methods, it can be produced for example by allowing a compound represented by the following formula (III): 
[wherein X3 is a substituent which serves as a leaving group, such as fluorine atom, chlorine atom, bromine atom, substituted or unsubstituted phenylsulfonyl group or a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms,
Y1 is the Y defined in the formula (I) or a boron-containing substituent represented by the following formula (IV):
xe2x80x94B(Y11)Y12xe2x80x83xe2x80x83(IV)
(wherein each of Y11 and Y12 is a fluorine atom or an alkylcarbonyloxy group having 2 to 4 carbon atoms), and R5, R6, R7, A1 and X1 are as defined in the formula (I)], or a compound represented by the following formula (V): 
[wherein R5, R6, R7, A1 and X1, X3 and Y1 are as defined in the formula (III)], to react with a compound represented by the following formula (VI): 
[wherein R31 is identical to the R3 defined in the formula (I) or a protective group of amino group, and R1, R2, R4 and n are as defined in the formula (I)] or an addition salt thereof.
The just described compound (VI) can be obtained by deprotecting the following compound in which the cyclic nitrogen atom is protected by a protective group. 
[In the above formula, Qxe2x80x2 is a protective group of amino group, and R311, R1, R2, R4 and n are as defined in the formula (I).]
The reaction can be carried out with or without using a solvent. The solvent to be used in the reaction may be any solvent which is inert under the reaction conditions, and its illustrative examples include dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, water, 3-methoxybutanol and the like or a mixture thereof.
Preferably, the reaction may be carried out in the presence of an acid receptor such as an inorganic base or an organic base, which includes an alkali metal or alkaline earth metal carbonate or bicarbonate or the like inorganic basic compound, or triethylamine, pyridine, 1,8-diazabicycloundecene or the like organic basic compound.
The reaction can be carried out at a temperature of from room temperature to 200xc2x0 C., preferably from 25 to 150xc2x0 C. The reaction is carried out for a period of from 30 minutes to 48 hours and completes generally after about 30 minutes to 2 hours.
Examples of the protecting groups of maino group include those which are generally used in this field, such as tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and the like alkoxycarbonyl groups, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, para-nitrobenzyloxycarbonyl and the like aralkyloxycarbonyl groups, acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl, benzoyl and the like acyl groups, tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, triphenylmethyl and the like alkyl or aralkyl groups, methoxymethyl, tert-butoxymethyl, tetrahydropyranyl, 2,2,2-trichloroethoxymethyl and the like ethers and trimethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, tribenzylsilyl, tert-butyldiphenylsilyl and the like silyl groups.
When Y and Y1 are an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and phenyl group, the compound of interest can be converted into its corresponding carboxylic acid by treating it under an acidic or basic condition which is generally employed for the hydrolysis of carboxylic acid esters.
When Y1 is a structure of the formula (IV), its conversion into corresponding carboxylic acid can be effected by allowing the compound (VI) to react with the compound (III) or (V) and then treating it under an acidic or basic condition.
In addition, when deprotection is required, the compound of interest represented by the formula (I) can be obtained by removing the protective group under appropriate procedure known in this field corresponding to the protective groups.
The compound of formula (VI) can be produced by various methods, and, though not particularly limited, it can be synthesized by a method shown in the reference examples as a preferred example.
The cis-2-fluorocyclopropylamine comprised of a single isomer, which is preferable for the synthesis of the compound of formula (I) comprised of a single isomer, can be synthesized for example by the method described in JP-A-2-231475 (the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d). Synthesis of the compound of formula (I) comprised of a single isomer can be carried out using the optically active cis-2-fluorocyclopropylamine derivative obtained in this-manner as the material, in accordance with the method described for example in JP-A-2-231475.
Since the compound of the present invention has strong antibacterial actions, it can be used as medicaments for use in human bodies, animals and fishes or as preservatives of agricultural chemicals and food.
When the compound of the present invention is used as a medicament for human bodies, its dosage is within the range of generally from 50 mg to 1 g, preferably from 100 mg to 300 mg, per day per adult.
Its dosage as a drug for animals varies depending on the purpose of its administration (healing or prevention), kind and size of each animal to be treated and kind and degree of each infected pathogenic bacterium, but the dosage may be within the range of generally from 1 mg to 200 mg, preferably from 5 mg to 100 mg, per 1 kg body weight per day.
The daily dose may be used once a day or by dividing it into 2 to 4 doses per day. As occasion demands, the daily dose may exceed the aforementioned range.
Since the compound of the present invention has activity against a broad range of microorganisms which cause various infectious diseases, it can treat, prevent or alleviate diseases induced by these pathogens.
Illustrative examples of bacteria and bacterioid microorganisms on which the compound of the present invention is effective include those which belong to the genus Staphylococcus, Streptococcus pyogens, hemolytic streptococcus, enterococcus, pneumococcus, those which belong to the genus Peptostreptococcus, Neisseria gonorrhoeae, Escherichia coli, those which belong to the genus Citrobacter, those which belong to the genus Shigella, Klebsiella pneumoniae, those which belong to the genus Enterobacter, those which belong to the genus Serratia, those which belong to the genus Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, those which belong to the genus Acinetobacter, those which belong to the genus Campylobacter, Chlamydia trachomatis and the like.
Illustrative examples of diseases which are induced by these pathogens include folliculitis, furuncle, carbuncle, erysipelas, phlegmon, lymphangitis, felon, subcutaneous abscess, hidradenitis, acne conglobata, infectious atheroma, perirectal abscess, mastitis, superficial secondary infections after injury, burn injury, operative wound and the like, pharyngitis, acute bronchitis, tonsilitis, chronic bronchitis, bronchiectasis, diffuse bronchiolitis, secondary infection of chronic respiratory disease, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethritis, nonspecific urethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis, uterine adnexitis, intrauterine infection, bartholinitis, blepharitis, hordeolum, dacryocystitis, tarsadenitis, corneal ulcer, octitis media, sinusitis, periodentitis, pericoronitis, jaw infection, peritonitis, endocarditis, sepsis, meningitis, skin infection and the like.
The inventive compound is also effective against various microorganisms which cause infectious diseases in animals, such as those which belong to the genera Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella, Staphylococcus, Mycoplasma and the like.
Illustrative examples of such diseases include colibacillosis, pullorum disease, avian paratyphoid, avian cholera, infectious coryza, staphylococcosis, mycoplasma infection and the like in the case of birds; colibacillosis, salmonellosis, pasteurellosis, haemophilus infection, atrophic rhinitis, exudative epidermis, mycoplasma infection and the like in the case of pigs; colibacillosis, salmonellosis, hemorrhagic sepsis, mycoplasma infection, bovine pleuropneumonia, bovine mastitis and the like in the case of cattle; colisepsis, salmonella infection, hemorrhagic sepsis, uterine empyema, cystitis and the like in the case of dogs; and exudative pleurisy, cystitis, chronic rhinitis, haemophilus infection, kitten diarrhea, mycoplasma infection and the like in the case of cats.
The antibacterial preparation which comprises the compound of the present invention can be prepared by selecting appropriate preparation depending on each administration method and employing generally used various preparation method. With regard to the dosage forms of the antibacterial preparation which uses the compound of the present invention as its principal agent, tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions and the like can be exemplified as oral preparations.
With regard to injections, a stabilizing agent, an antiseptic agent, a solubilizing agent and the like may be used in the preparation, and a solution which may contain these auxiliary agents may be contained in a container and made into a solid preparation by freeze-drying or the like means to be re-dissolved when used. In addition, a single dose may be contained in a single container or multiple doses may be contained in the same container.
Also, solutions, suspensions, emulsions, ointments, gels, creams, lotions, sprays and the like can be exemplified as preparations for external use.
Solid preparations may contain pharmaceutically acceptable additives together with the active compound and can be prepared for example by mixing the compound with additives optionally selected from fillers, extenders, binders, disintegrators, solubilization enhancing agents, moistening agents, lubricating agents and the like. As liquid preparations, solutions, suspensions, emulsions and the like can be exemplified, which may contain a suspending agent, an emulsifying agent and the like as additives.
Examples of the method for administering the compound of the present invention to animals include a method in which it is orally administered directly or by mixing it with feed, a method in which it is made into a solution and then orally administered directly or by mixing it with drinking water or feed and a method in which it is administered by injection. With regard to the pharmaceutical preparations for use in the administration of the compound of the present invention to animals, it can be made optionally into powders, fine subtilaes, soluble powders, syrups, solutions or injections making use of the techniques generally used in this field.
Formulation examples of the pharmaceutical preparations are shown below.